tbuckley/cabot-search huggingface dataset:
Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis
Authors: Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom DiMaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis
Journal: Journal of Clinical Investigation (2022)

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan–binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1–dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α– and IL-1β–mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.
Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects
Authors: Edmone Dewaeles, Kévin Carvalho, Sandy Fellah, Jaewon Sim, Nihad Boukrout, Raphaelle Caillierez, Hariharan Ramakrishnan, Cynthia Van der Hauwaert, Jhenkruthi Vijaya Shankara, Nathalie Martin, Noura Massri, Agathe Launay, Joseph K. Folger, Clémentine de Schutter, Romain Larrue, Ingrid Loison, Marine Goujon, Matthieu Jung, Stéphanie Le Gras, Victoria Gomez-Murcia, Emilie Faivre, Julie Lemaire, Anne Garat, Nicolas Beauval, Patrice Maboudou, Viviane Gnemmi, Jean-Baptiste Gibier, Luc Buée, Corinne Abbadie, Francois Glowacki, Nicolas Pottier, Michael Perrais, Rodrigo A. Cunha, Jean-Sébastien Annicotte, Geoffroy Laumet, David Blum, Christelle Cauffiez
Journal: Journal of Clinical Investigation (2022)

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.
Does treating with anti–PD-1 to improve glomerular health come without a cost?
Authors: Kenar D Jhaveri, Abhijat Kitchlu, Ala Abudayyeh
Journal: Journal of Clinical Investigation (2022)

We read with great interest the study by Pippin et al. (1) that highlighted the anti-aging effect of the podocyte with anti-programmed cell 1 death (anti-PD-1) antibodies.In addition, the authors elegantly showed that administration of anti-PD-1 antibody treatment to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved total podocyte counts.Clinically, as practicing onco-nephrologists, we have seen patients with use of immune checkpoint inhibitors (ICIs), specifically anti-PD-1 agents, and new-onset glomerular disease.In general, the incidence of acute kidney injury (AKI) via kidney immune-related adverse events was 2% to 3% in a large multicenter study (1, 2).Acute interstitial nephritis has been reported as the most common kidney biopsy finding, although many glomerular lesions have been reported.Pauci-immune vasculitis, podocytopathies (including minimal change disease and FSGS), and C3 glomerulonephritis (GN) have been the most common glomerular diseases described.In an analysis of all published case reports and
Letter by Sherratt Regarding Article, “Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy”
Authors: Samuel C.R. Sherratt
Journal: Circulation (2022)
Loss of function of the nuclear envelope protein LEMD2 causes DNA damage–dependent cardiomyopathy
Authors: Xurde M. Caravia, Andres Ramirez-Martinez, Peiheng Gan, Feng Wang, John R. McAnally, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N. Olson
Journal: Journal of Clinical Investigation (2022)

Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, that primarily affect the heart and skeletal muscle. A mutation in the NEP LEM domain–containing protein 2 (LEMD2) causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. We generated knockin (KI) mice carrying the human c.T38>G Lemd2 mutation, which causes a missense amino acid exchange (p.L13>R) in the LEM domain of the protein. These mice represent a preclinical model that phenocopies the human disease, as they developed severe dilated cardiomyopathy and cardiac fibrosis leading to premature death. At the cellular level, KI/KI cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of Lemd2 also died shortly after birth due to heart abnormalities. Cardiomyocytes lacking Lemd2 displayed nuclear envelope deformations and extensive DNA damage and apoptosis linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus rescued cardiac function in KI/KI mice. Together, our results reveal the essentiality of LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.
Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell–mediated antitumor immunity
Authors: Xiaoxin Ren, Mou Peng, Peng Xing, Yao Wei, Phillip M. Galbo, Devin Corrigan, Hao Wang, Yingzhen Su, Xiaoshen Dong, Qizhe Sun, Yixian Li, Xiaoyu Zhang, Winfried Edelmann, Deyou Zheng, Xingxing Zang
Journal: Journal of Clinical Investigation (2022)

Cancer immunotherapy targeting the TIGIT/PVR pathway is currently facing challenges. KIR2DL5, a member of the human killer cell, immunoglobulin-like receptor (KIR) family, has recently been identified as another binding partner for PVR. The biology and therapeutic potential of the KIR2DL5/PVR pathway are largely unknown. Here we report that KIR2DL5 was predominantly expressed on human NK cells with mature phenotype and cytolytic function and that it bound to PVR without competition with the other 3 known PVR receptors. The interaction between KIR2DL5 on NK cells and PVR on target cells induced inhibitory synapse formation, whereas new monoclonal antibodies blocking the KIR2DL5-PVR interaction robustly augmented the NK cytotoxicity against PVR+ human tumors. Mechanistically, both intracellular ITIM and ITSM of KIR2DL5 underwent tyrosine phosphorylation after engagement, which was essential for KIR2DL5-mediated NK suppression by recruiting SHP-1 and/or SHP-2. Subsequently, ITIM/SHP-1/SHP-2 and ITSM/SHP-1 downregulated the downstream Vav1/ERK1/2/p90RSK/NF-κB signaling. KIR2DL5+ immune cells infiltrated in various types of PVR+ human cancers. Markedly, the KIR2DL5 blockade reduced tumor growth and improved overall survival across multiple NK cell-based humanized tumor models. Thus, our results revealed functional mechanisms of KIR2DL5-mediated NK cell immune evasion, demonstrated blockade of the KIR2DL5/PVR axis as a therapy for human cancers, and provided an underlying mechanism for the clinical failure of anti-TIGIT therapies.
Annexin A2/TLR2/MYD88 pathway induces arginase 1 expression in tumor-associated neutrophils
Authors: Huajia Zhang, Xiaodong Zhu, Travis J. Friesen, Jeff W. Kwak, Tatyana Pisarenko, Surapat Mekvanich, Mark A. Velasco, Timothy W. Randolph, Julia Kargl, A. McGarry Houghton
Journal: Journal of Clinical Investigation (2022)

Myeloid lineage cells suppress T cell viability through arginine depletion via arginase 1 (ARG1). Despite numerous studies exploring the mechanisms by which ARG1 perturbs lymphocyte function, the cellular populations responsible for its generation and release remain poorly understood. Here, we showed that neutrophil lineage cells and not monocytes or macrophages expressed ARG1 in human non-small cell lung cancer (NSCLC). Importantly, we showed that approximately 40% of tumor-associated neutrophils (TANs) actively transcribed ARG1 mRNA. To determine the mechanism by which ARG1 mRNA is induced in TANs, we utilized FPLC followed by MS/MS to screen tumor-derived factors capable of inducing ARG1 mRNA expression in neutrophils. These studies identified ANXA2 as the major driver of ARG1 mRNA expression in TANs. Mechanistically, ANXA2 signaled through the TLR2/MYD88 axis in neutrophils to induce ARG1 mRNA expression. The current study describes what we believe to be a novel mechanism by which ARG1 mRNA expression is regulated in neutrophils in cancer and highlights the central role that neutrophil lineage cells play in the suppression of tumor-infiltrating lymphocytes.
BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer
Authors: Kun Li, Yanan Liu, Yi Ding, Zhengwei Zhang, Juanjuan Feng, Jiaxin Hu, Jiwei Chen, Zhengke Lian, Yiliang Chen, Kewen Hu, Zhi Chen, Zhenyu Cai, Mingyao Liu, Xiufeng Pang
Journal: Journal of Clinical Investigation (2022)

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.
STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma
Authors: Connor P. Hall, James C. Cronk, Jeffrey A. Rubens
Journal: Journal of Clinical Investigation (2022)

Pediatric high-grade gliomas (pHGGs) are aggressive diseases with poor outcomes. The diverse molecular heterogeneity in these rare tumors and inadequate tumor models have limited the development of effective therapies. In this issue of the JCI, Haase et al. produced a genetically engineered mouse model of H3.3-G34R–mutant pHGG to help identify vulnerabilities in DNA repair pathways. The authors designed a therapy that combined radiation with DNA damage response inhibitors to induce an adaptive immune response and extend survival. These findings suggest that combinations of small-molecule therapies with immunotherapies could drive a more durable response and improve mortality for patients with pHGG.
Safety of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis
Authors: Alexandre Sepriano, Andreas Kerschbaumer, Sytske Anne Bergstra, Josef S Smolen, Désirée van der Heijde, Roberto Caporali, Christopher J Edwards, Patrick Verschueren, Savia de Souza, Janet Pope, Tsutomu Takeuchi, Kimme Hyrich, Kevin L Winthrop, Daniel Aletaha, Tanja Stamm, Jan W Schoones, Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2022)

To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.
Prospective evaluation of smartwatch-enabled detection of left ventricular dysfunction
Authors: Zachi I. Attia, David M. Harmon, Jennifer Dugan, Lukas Manka, Francisco Lopez-Jimenez, Amir Lerman, Konstantinos C. Siontis, Peter A. Noseworthy, Xiaoxi Yao, Eric W. Klavetter, John D. Halamka, Samuel J. Asirvatham, Rita Khan, Rickey E. Carter, Bradley C. Leibovich, Paul A. Friedman
Journal: Nature Medicine (2022)
Pathophysiology, diagnosis, and management of endometriosis
Authors: Andrew W Horne, Stacey A Missmer
Journal: BMJ (2022)

Endometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.
Association of COVID-19 Vaccination With Influenza Vaccine History and Changes in Influenza Vaccination
Authors: Andrew M. Parker, Samer Atshan, Matthew M. Walsh, Courtney A. Gidengil, Raffaele Vardavas
Journal: JAMA Network Open (2022)

This survey study assesses how COVID-19 vaccination differs across historical influenza vaccination patterns and whether influenza vaccination changed during the COVID-19 pandemic.
Symptoms of Anxiety and Depression Among Adolescents Before vs During COVID-19–Related School Closures in China
Authors: Miao Qu, Kun Yang, Yujia Cao, Xue Wang, Shuping Tan, Meihong Xiu, Xiangyang Zhang
Journal: JAMA Network Open (2022)

This cohort study compares the psychological status of Chinese adolescents at school before the COVID-19 pandemic and at home during the pandemic to assess whether school attendance was associated with negative mental health outcomes.
Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal
Authors: Caroline M. Mitchell, Joseph C. Larson, Carolyn J. Crandall, Shalender Bhasin, Andrea Z. LaCroix, Kristine E. Ensrud, Katherine A. Guthrie, Susan D. Reed
Journal: JAMA Network Open (2022)

Half of women who are postmenopausal have genitourinary discomfort after menopause. Recommended therapies include low-dose vaginal estrogen. Individuals with a history of breast cancer or venous thromboembolism may have concerns about the safety of this intervention.To compare serum estrogen concentrations with the use of vaginal estrogen, 10 μg, tablet vs placebo in women who are postmenopausal.This is a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to severe genitourinary syndrome in women who are postmenopausal. The study was conducted at Kaiser Permanente Washington Health Research Institute and the University of Minnesota from April 11, 2016, to April 23, 2017. Measurements and data analysis were performed from November 3, 2020, to September 23, 2022.Participants were randomly assigned to vaginal estradiol tablet (10 μg/d for 2 weeks and then twice weekly) plus placebo gel (3 times weekly) or dual placebo for 12 weeks.In this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone-binding globulin (SHBG) concentrations were measured by a chemiluminescent assay. Week 12 values of the 3 analytes were compared by baseline participant characteristics. Linear models compared week 12 estradiol concentrations between treatment groups, adjusted for baseline characteristics.A total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations.In this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain.ClinicalTrials.gov Identifier: NCT02516202.
Long-term Cognitive Trajectory After Total Joint Arthroplasty
Authors: Maria Vassilaki, Walter K. Kremers, Mary M. Machulda, David S. Knopman, Ronald C. Petersen, Mariana L. Laporta, Daniel J. Berry, David G. Lewallen, Hilal Maradit Kremers
Journal: JAMA Network Open (2022)

Importance Individuals with total joint arthroplasty (TJA) have long-term exposure to metal-containing implants; however, whether long-term exposure to artificial implants is associated with cognitive function is unknown. Objective To compare long-term cognitive trajectories in individuals with and without TJA. Design, Setting, and Participants This population-based cohort study assessed serial cognitive evaluations of 5550 participants (≥50 years of age) from the Mayo Clinic Study of Aging between November 1, 2004, and December 31, 2020. Exposures Total joint arthroplasty of the hip or the knee. Main Outcomes and Measures Linear mixed-effects models were used to compare the annualized rate of change in global and domain-specific cognitive scores in participants with and without TJA, adjusting for age, sex, educational level, apolipoprotein E ε4 carrier status, and cognitive test practice effects. Results A total of 5550 participants (mean [SD] age at baseline, 73.04 [10.02] years; 2830 [51.0%] male) were evaluated. A total of 952 participants had undergone at least 1 TJA of the hip (THA, n = 430) or the knee (TKA, n = 626) before or after entry into the cohort. Participants with TJA were older, more likely to be female, and had a higher body mass index than participants without TJA. No difference was observed in the rate of cognitive decline in participants with and without TJA until 80 years of age. A slightly faster cognitive decline at 80 years or older and more than 8 years from surgery was observed (b = −0.03; 95% CI, −0.04 to −0.02). In stratified analyses by surgery type, the faster decline was observed primarily among older participants with TKA (b = −0.04; 95% CI, −0.06 to −0.02). Conclusions and Relevance In this cohort study, long-term cognitive trajectories in individuals with and without TJA were largely similar except for a slightly faster decline among the oldest patients with TKA; however, the magnitude of difference was small and of unknown clinical significance.